Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

EBV-associated Malignancies Clinical Trial

Official title:

A Phase II Study of the Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01498484
• Other study ID #: 11-130
• Status: Completed
• Phase: Phase 2
• Start date: December 2011
• Est. completion date: July 2019

Study information

• Verified date: September 2022
• Source: Atara Biotherapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase II trial to evaluate the efficacy and safety of human leukocyte antigen (HLA) partially-matched third-party allogeneic Epstein-Barr virus cytotoxic T lymphocytes (EBV-CTLs) for the treatment of EBV-induced lymphomas and EBV-associated malignancies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: July 2019
• Est. primary completion date: July 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma or other EBV-associated malignancy. OR
• Evaluable disease as demonstrated by clinical and/or radiologic studies with current or prior elevated blood levels of EBV DNA exceeding 500 copies/ml by quantitative real time polymerase chain reaction (PCR). OR
• Persistent or recurrent elevations in levels of EBV DNA exceeding 500 copies/ml in patients previously treated for EBV-LPD with chemotherapy and/or rituximab who do not yet have clinically or radiologically evaluable disease but are at high risk of disease recurrence.
• EBV-specific T cells are available for adoptive immune cell therapy from a consenting third party donor. The third party EBV-CTLs to be administered will be selected on the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and 2) that they are restricted by an allele shared with the EBV+ malignancy (if known), or with the donor in HSCT recipients, or patient in organ transplant or immunodeficient patients
• KPS or Lansky score = 20.
• A life expectancy of at least 6 weeks.
• Adequate bone marrow, heart, lung, liver and kidney function at the time of treatment

with EBV-specificT cells is initiated, including:

1. Absolute neutrophil count (ANC) = 1,000/µL, with or without GCSF support

2. Platelets = 20,000/µL

3. Creatinine = 2.0mg/dl

4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3.0x and total bilirubin < 2.5x the institutional upper limit of normal (ULN)

5. Stable blood pressure and circulation not requiring pressor support

6. Adequate cardiac function as demonstrated by EKG and/or echocardiographic evidence (may be performed within 30 days prior to treatment)

• However, abnormalities of specific organs will not be considered grounds for exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a renal allograft recipient with an EBV LPD may be on dialysis because the allograft was rejected when the immune suppression was stopped as a first approach to treatment of the EBV LPD). At the discretion of the investigator, patients with elevated but stable creatinine will not be precluded from treatment on study.
• There is no age restriction to eligibility for this protocol. It is expected that five types of patients afflicted with EBV-associated lymphomas, lymphoproliferative diseases or malignancies will be referred and will consent to

participate in this trial. These are:

1. Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie, marrow, PBSC, or umbilical cord blood).

2. Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic organ transplant.

3. Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a consequence of the profound acquired immunodeficiency induced by HIV.

4. Patients who develop EBV lymphomas or lymphoproliferative diseases or other EBV-associated malignancy as a consequence of profound immunodeficiencies associated with a congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive therapy.

5. Patients who develop other EBV-associated malignancies without pre-existing immune deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma. Exclusion Criteria:

The following patients will be excluded from this study:

• Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment
• Patients who are pregnant
• Patients with severe comorbidities, not related to their EBV-associated malignancy, that would be expected to preclude their survival for the 6 weeks required to assess response of T cell therapy
• Patients eligible for MSK protocol #16-803 (EBV-CTL-201)

Related Conditions & MeSH terms

• EBV-associated Malignancies
• EBV-induced Lymphomas
• Epstein-Barr Virus Infections
• Lymphoma
• Lymphoproliferative Disorders
• Neoplasms
• Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma
• Viremia

Intervention

Biological:
• EBV-specific T cells (EBV-CTLs)
EBV-CTLs are cytotoxic T lymphocytes that specifically kill cells presenting EBV protein antigens including EBV-transformed B lymphocytes responsible for EBV-associated lymphomas and lymphoproliferative disorders.

Locations

Country	Name	City	State
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Atara Biotherapeutics	Memorial Sloan Kettering Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	The ORR is defined as percentage of participants with best overall response of complete remission/response (CR) or partial remission/response (PR) based on investigator's assessment. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR is complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of the affected tissues when indicated, lasting for at least 3 weeks following completion of a cycle of tabelecleucel; and PR is a 50 % or greater reduction in the size of all lymphomatous lesions as determined by computed tomography (CT) or magnetic resonance imaging (MRI) measurements of tumor volume, which was maintained for at least 3 weeks following completion of a cycle of tabelecleucel. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR is clearance of EBV without subsequent development of EBV+ LPD; and PR is at least a 10-fold decrease in EBV DNA levels.	From Day 1 through 65.3 months after Day 1 dose
Secondary	Overall Survival (OS)	The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.	From Day 1 through 65.3 months after Day 1 dose
Secondary	OS Rate at 12 Months	Percentage of participants with OS at 12 months are reported. The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.	From Day 1 through 12 months after Day 1 dose
Secondary	OS Follow-up Time	The OS follow-up time are reported. The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.	From Day 1 through 65.3 months after Day 1 dose
Secondary	Time to Response (TTR)	The TTR is defined as the time from the date of the first dose of tabelecleucel to the date of a PR or CR, whichever occurred first. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR is defined as complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of the affected tissues when indicated, lasting for at least 3 weeks following completion of a cycle of tabelecleucel; and a PR is defined as a 50 % or greater reduction in the size of all lymphomatous lesions as determined by CT or MRI scan measurements of tumor volume, which was maintained for at least 3 weeks following completion of a cycle of tabelecleucel. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR is defined as clearance of EBV without subsequent development of EBV+ LPD; and PR is defined as at least a 10-fold decrease in EBV DNA levels.	From Day 1 through 65.3 months after Day 1 dose

External Links

•   Memorial Sloan Kettering Cancer Center